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Methylmalonate Overload Despite Glycemic Control Drives Diabetic Heart Damage
Shanjie Wang1,2, Miao Yan1,2, Yiying Zhang3
1Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, China (S.W., M.Y., Y.W., J.G., Z.C., X. Liu, Z.L., R.L., G.M., P.W., Y.H., Y.L., Zeng Wang, X. Luo, H.C., Zhuozhong Wang, S.Y., S.F., B.Y.).
Circulation Research
|July 29, 2026
Summary
Methylmalonic acid (MMA) accumulation, not linked to cobalamin (Cbl) deficiency, drives heart damage in diabetes. Metformin shows promise in mitigating MMA-induced cardiac issues, challenging current treatment assumptions.
Area of Science:
- Cardiology
- Metabolic Disorders
- Biochemistry
Background:
- Diabetic patients face a high heart failure burden despite glycemic control, linked to metabolic remodeling.
- Methylmalonic acid (MMA) elevation is paradoxically associated with increased cardiovascular mortality in diabetic patients with normal or high cobalamin (Cbl) levels.
- The mechanisms behind this contradictory MMA accumulation in the diabetic heart are not well understood.
Purpose of the Study:
- To investigate the mechanisms and translational significance of MMA accumulation in the diabetic heart.
- To explore the role of methylmalonyl-CoA mutase (Mmut) in MMA dysmetabolism in diabetes.
- To assess the impact of Cbl supplementation and metformin on MMA-related cardiac damage.
Main Methods:
- Analysis of serum Cbl, MMA, and cardiac biomarkers in a large human cohort (12,751 participants).
- Characterization of Mmut expression in human diabetic failing hearts.
- Utilized cardiomyocyte-specific Mmut knockout and Mmut-overexpressing mouse models of diabetes.
- Employed 13C-isotope tracing, RNA sequencing, immunoprecipitation, and biolayer interferometry to elucidate molecular mechanisms.
Main Results:
- Elevated serum MMA correlated with subclinical heart damage and adverse outcomes in diabetic adults, irrespective of Cbl deficiency.
- Decreased Mmut expression and increased cardiac MMA were observed in diabetic humans and mice, preceding cardiac dysfunction.
- miR-499 was identified as a regulator of Mmut expression, exacerbating MMA accumulation; branched-chain amino acid restriction and Mmut overexpression attenuated cardiac damage.
- Cbl supplementation was ineffective, while metformin mitigated MMA-induced heart damage by activating AMPK-dependent mitochondrial quality control and promoting Mmut-Cbl cooperation.
Conclusions:
- Diabetes-related MMA dysmetabolism triggers subclinical heart damage resistant to glycemic control and Cbl supplementation.
- Findings challenge the clinical consensus on Cbl and metformin's impact on MMA levels in diabetic management.
- This study provides a foundation for understanding MMA as a therapeutic target in diabetic cardiomyopathy.
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